The present invention relates to methods of treating cancer in which histamine is administered in conjunction with other cancer therapies. The cancer therapy includes surgery, radiation, immunotherapy, the administration of an agent which enhances the humoral immune response of the patient or any combination thereof.
Despite tremendous advances over the past several years, current cancer therapies fail to cure many forms of cancer. The problems faced by investigators and clinicians are numerous. Some tumors are not resectable or do not respond to radiation or chemotherapy or combinations of these procedures. Furthermore, the severe morbidity often associated with these treatments has led many to look for entirely new approaches to tumor therapy that are more specifically lethal for cancer cells and less toxic for normal cells. Attempts to promote an immune response to the tumor by immunizing the cancer patient with killed cancer cells or antigens specific for cancer cells have been largely unsuccessful and the use of monoclonal antibodies (mAbs) as the xe2x80x9cmagic bulletxe2x80x9d to specifically destroy cancer cells without harming normal cells remains clinically limited. Methods that enhance the effectivity of known cancer therapies are desperately needed.
Surgery is touted by many to be the only potentially curative therapy for patients suffering from stomach, pancreatic, carcinoid and ovarian tumors. (Norton, Digestion 55(suppl 3):98-103 (1994)). Although surgery is often the indicated treatment for malignant disease, this form of cancer therapy has two major shortcomings. First, many tumors are not resectable because they are located in or have spread into vital structures. (Dvorak et al., Cancer Cells 3: 77-85 (1991)). While debulking of tumors in vital areas has been presented as an alternative, such procedures are felt by many to inadequately treat the disease and only improve the quality of life of the patient. (Norton, Digestion 55(suppl 3):98-103 (1994)). Second, by the time of diagnosis and removal of the primary tumor, many tumors have already metastasized. (Dvorak et al., Cancer Cells 3: 77-85 (1991)) and (Norton, Digestion 55(suppl 3):98-103 (1994)). Metastases, which tend to be multiple and wide spread, do not easily lend themselves to surgical excision and, consequently, many patients undergo major surgical procedures only to have rapid disease progression found soon after surgery. (Dvorak et al., Cancer Cells 3: 77-85 (1991)). While surgery remains a good first line of defense against cancer, oncologists are now also combining other treatment methods including radiation, chemotherapy and immunotherapy to obtain better patient survival. (Hacker and van der Burg, Annals of Oncology 4 (suppl. 4): S17-S22 (1993)).
External beam radiation has replaced surgery for the long-term control of many tumors of the head and neck, cervix, bladder, prostate and skin, in which it often achieves a reasonable probability of tumor control with good cosmetic result. (Basic Clinical Radiobiology 2nd edition. Steel ed., Arnold Publishers, pp. 1-13 (1997)). External beam radiation is generally helpful for the treatment of localized tumors but this approach is also problematic because it causes considerable damage to surrounding cells and compromises the patient""s immune system. The use of radioactive xe2x80x9cseed implantsxe2x80x9d has provided more focus on tumor cells and less damage to surrounding tissue but a more specific means to deliver radiation to the tumor is needed. While radiation therapy is a good alternative to surgery, it is unable to treat a large percentage of cancers that are radiation-insensitive and, because of the high morbidity associated with high doses of external beam radiation, the use of radiation to treat metastastic disease is not desirable. (Dvorak et al., Cancer Cells 3: 77-85 (1991)).
Many forms of antibody therapy to treat cancer have also been reported. Early antibody therapy treatments relied almost entirely on complement fixation to kill tumor cells. (Cellular and Molecular Immunology. Eds. Abul K Abbas, Andrew H. Lichtman, and Jordan S. Pober, W. B. Saunders Co., Philadelphia (1991)). Recently, greater success has been achieved using antibodies which block cancer cell growth factor receptors. (Wong, Genetic Engineering News pp.23 and 49 (July 1998) and Ashley et al., J of Neuro-Oncology 35:259-273 (1997)). The use of antibody conjugates which bind tumor cells with cytotoxic substances such as toxic molecules or radioisotopes has also seen promising results. (Larson et al., ACTA Oncologica 32:709-715 (1993); Quack and van Dongen, Eur Arch Otorhinolaryngol 251:1-5 (1994); Frankel et al., Cancer Biology 6:307-317 (1995); Mach et al., Curr Op in Immunol 3:685-693 (1191) and Recent Results in Cancer Research vol 141:Systemic Radiotherapy with Monoclonal Antibodies. edited by M. L. Sautter-Bihl and M Wannenmacher, Springer-Verlag publishers, (1996)). Another innovative antibody treatment for cancer uses antibody heteroconjugatesxe2x80x94dual purpose antibodies which direct bound cancer cells to phagocytic cells of the immune system. (Wong, Genetic Engineering News pp.23 and 49 (July 1998)). Preliminary clinical trials with mAb heteroconjugates have shown promise in the treatment of renal and prostate cancer. (Id.).
Although a variety of tumor cells can be lysed in vitro by antibody-dependent mechanisms such as complement activation or antibody-dependent cell-mediated cytotoxicity, few therapies based on enhancing the humoral response of a subject have been clinically successful. (Sedlacek, Critical Reviews in Oncogenesis 5(6):555-587 (1994)). In one study, patients suffering from melanoma were administered a vaccine containing a mixture of three allogenic melanoma cell lines and showed a 71% 10-year actuarial survival as opposed to the 40% 10-year actuarial survival demonstrated by melanomic patients who received a single cell line vaccine. (Slingluff and Seigler, Ann Plast Surg 28:104-107 (1992)). In another study, however, leukemic patients immunized with killed leukemia cells failed to demonstrate any significant improvement. (Cellular and Molecular Immunology. Eds. Abul K Abbas, Andrew H. Lichtman, and Jordan S. Pober, W. B. Saunders Co., Philadelphia (1191)).
In an attempt to improve cancer vaccines, researchers have tried numerous strategies to make the cancer cell vaccines more antigenic. (Sedlacek, Critical Reviews in Oncogenesis 5(6):555-587 (1994)). Studies on immunization with plasmid DNA encoding defined tumor antigens or with a complex comprising hydrophobized polysaccharides attached to an oncogenic receptor protein, for example, may show greater clinical success. (Tuting et al., J Mol Med 75:478-491 (1997) and Gu et al. Cancer Research 58:3385-3390 (1998)). At present investigators have had limited success with treating cancer by administering agents which enhance the humoral response of the patient and approaches to improve the effectivity of this form of treatment are needed.
Despite recent progress in cancer therapy, many problems persist. Tumors often metastasize, grow in sensitive areas and are not treatable by surgery or radiation. (Dvorak et al., Cancer Cells 3: 77-85 (1191)). Tumor cells also generally avoid immunosurveillance in the cancer patient and most current vaccines poorly trigger a cancer patient""s immune system to overcome this immunotolerant state. (Sedlacek; Critical Reviews in Oncogenesis 5(6):555-587 (1994)). Further, the use of antibody therapies such as immunotoxins, immunoradionuclides, immunoheteroconjugates, and receptor specific antibodies has been limited by low-level expression of the targeted tumor associated antigen, low-affinity mAbs, inefficient radionuclides, non-specific toxicity of the antibody conjugate and poor tumor uptake of the therapeutic agent. (Ashley et al., J of Neuro-Oncology 35:259-273 (1997); Frankel et al., Cancer Biology 6:307-317 (1995); Mach et al., Curr Op in Immunol. 3:685-693 (1191) and Sedlacek, Critical Reviews in Oncogenesis 5(6):555-587 (1994)). The need for an agent that enhances current methods of cancer therapy has long been manifest.
The present invention provides novel methods of treating cancer in which histamine is administered in conjunction with conventional cancer therapies such as surgery, radiation, immunotherapy, and agents which enhance the humoral immune response of the patient. In one embodiment, a method of augmenting a cancer therapy encompasses administering to a subject a pharmaceutically acceptable form of histamine over a period of time such that a blood histamine concentration sufficient to augment the cancer therapy is achieved and administering to the subject a cancer therapy such as surgery, radiation, immunotherapy and an agent which enhances the humoral response of the subject.
Preferably, a pharmaceutically acceptable form of histamine is used such as histamine, histamine dihydrochloride, histamine phosphate, histamine salts, esters, congeners, prodrugs, histamine receptor agonists and diphenyleneiodonium. The types of radiation therapy which can be used include external beam radiation, radionuclides, radioactive implants, radioactive antibodies, radioactive lipids, radioactive proteins, radioactive glycolipids and radioactive glycoproteins. The types of immunotherapy which can be used include the administration of a monoclonal antibody, a humanized monoclonal antibody, an Fab, an (Fabxe2x80x2)2, an Fv, an antibody conjugate, an Fab conjugate, an (Fabxe2x80x2)2 conjugate, an Fv conjugate and an antibody heteroconjugate. Several types of agents which enhance the humoral response of the subject can be used including viral antigens, cancer cell antigens, inactivated cancer cells, vaccines, and vitamers.
Histamine is administered in such a manner that a stable blood histamine concentration is maintained during the administration of the cancer therapy to the subject. Histamine can be administered to the subject indirectly by administering a substance which induces the release of endogenous histamine such as retinoic acid, a retinoid, IL-3 or an ingestible allergen. Histamine can be administered prior to administering the cancer therapy, after administering the cancer therapy, or during administration of the cancer therapy. Furthermore, histamine is administered in a dose from 0.1 to 10.0 milligrams per day.
In another embodiment, the invention provides a method of screening cancer treatments in which a non-human mammal, having been grafted with human tumor cells, is administered histamine and a cancer therapy, such as a radioactive substance, an antibody, an agent that enhances the humoral immune response of the non-human mammal, radiation, or surgery. After administering the cancer therapy, the tumorcidal response of the non-human mammal is then determined at various time points. According to this method, monoclonal antibodies, monoclonal antibodies conjugated to a compounds such as a toxin, a radioactive substance, a radionuclide, an antibody fragment or a second antibody, a vaccine (including killed cancer cells), a radioactive seed implant or external beam radiation can be used.
Histamine is a biogenic amine, i.e., an amino acid that possesses biological activity mediated by pharmacological receptors after decarboxylation. The role of histamine in immediate-type hypersensitivity is well-established. (Plaut, M. and Lichtenstein, L. M, 1982, Histamine and Immune Responses in Pharmacology of Histamine Receptors. Ganellin, C. R. and M. E. Parsons, eds. John Wright and Sons, Bristol, pp. 392-435). Histamine also mediates arteriole dilation which causes a rise in capillary and venule pressure. (Majno et al., J Cell Bio 42:647-672 (1969)). Furthermore, histamine induces contraction of endothelial cells resulting in the formation of intercellular gaps and extravasation of blood vessels. (Id.).
The present invention is based on the unexpected discovery that histamine produces a synergistic tumorcidal response when it is administered in conjunction with surgery, radiation, antibody therapy or agents which enhance the humoral response of a cancer patient.
By xe2x80x9chistaminexe2x80x9d is meant histamine, its dihydrochloride salt (histamine dihydrocholride), histamine phosphate, other histamine salts, esters, or prodrugs, and histamine receptor (H1, H2, H3) agonists. Seratonin, bradykinin, diphenyleneiodonium and 5HT agonists are also contemplated. Other analogs of histamine or histamine receptor agonists that are suitable for use in the present invention are disclosed in U.S. Pat No. 5,728,378 and are known to those of skill in the art. The administration of compounds which induce the release of endogenous histamine from the patient""s own tissues are also included within the scope of the present invention; thus, the term xe2x80x9chistaminexe2x80x9d as used herein incorporates these compounds as well.
By xe2x80x9ccancer therapyxe2x80x9d is meant surgery, radiation, chemotherapy, antibody therapy and agents which enhance the humoral immune response of a patient suffering from cancer. xe2x80x9cCancer therapyxe2x80x9d may also include combinations of the treatments mentioned above. It will be appreciated by those skilled in the art that several combinations of the above cancer therapy methods produce synergistic effects on malignancies. Optimization of such combination treatment protocols in conjunction with histamine treatment, as detailed below, would be routine.
By xe2x80x9csurgeryxe2x80x9d is meant surgical procedures to remove cancer cells from a patient including but not limited to tumor resection and/or debulking of a tumor. Established methods of surgical oncology vary according to the type of tumor and the patient""s particular situation. Examples of surgical techniques are found in Surgical Oncolog edited by Raphael E. Pollock; Kluwer Academic Publishers, 1997.
By xe2x80x9cradiation therapyxe2x80x9d is meant the application of external beam radiation or the administration of radioactive substances to a cancer patient including but not limited to radionuclides, radioactive implants, radioactive antibodies or radioactive proteins. Many approaches to radiation therapy are known in the art and examples can be found in Basic Clinical Radiobiology (second edition), edited by G. Gordon Steel, Arnold publishers, 1997.
By xe2x80x9cantibody therapyxe2x80x9d is meant the administration of an antibody, an antibody conjugate or an antibody heteroconjugate to a cancer patient for the purpose of treating or preventing cancer. Many forms of antibody therapy are known in the art including, but not limited to, the administration of monoclonal or humanized monoclonal antibodies, the administration of toxin or radionuclide conjugated antibodies and the administration of monoclonal antibody heteroconjugates having one domain that binds to a cancer antigen and another domain that binds to the Fc region of IgG. Further, the term antibody therapy is meant to include the administration of (Fabxe2x80x2)2 or Fab fragments with or without conjugated toxins or radionuclides. Several examples of antibody therapy are found in Recent Results in Cancer Research vol 141:Systemic Radiotherapy with Monoclonal Antibodies, edited by M. L. Sautter-Bihl and M. Wannenmacher, Springer-Verlag publishers, 1996.
By xe2x80x9cagents which enhance the humoral immune responsexe2x80x9d is meant substances which are administered to a cancer patient for the purpose of enhancing their humoral immune response. Many methods of enhancing the humoral immune response of a patient suffering with cancer are known, including but not limited to, the administration of viral antigens, cancer cell antigens, inactivated cancer cells, vaccines and vitamers including ascorbic acid, tocopherol and betacarotene.
The administration of histamine can follow several treatment regimens and the following protocols are meant to exemplify some of the ways to use the present invention but they are not intended to limit the scope of the present discovery. The present invention includes the delivery of a beneficial amount of histamine to the cancer patient before, during or after the administration of an established form of cancer therapy such as surgery, radiation, antibody therapy or an agent which enhances the humoral immune response of the patient.
Beneficial levels of circulating blood histamine are obtained by administering histamine at a dosage of around 0.1 to 10.0 mg/day, preferably around 0.5 to 8.0 mg/day and more preferably around 1.0 to 5.0 mg/day. In a further embodiment, the histamine is administered over a period of 1-4 weeks. In a highly preferred embodiment, the histamine is administered for a period of 1-2 weeks. In one embodiment of the invention, a beneficial stable level of circulating blood histamine concentration (i.e a stable level of circulating blood histamine concentration of at least about 0.2 xcexcM) is maintained.
It will be appreciated by those of skill in the art that the patient""s circulating blood histamine level can also be monitored during the course of treatment and boosted whenever the level drops below the beneficial level or approaches the lower limits of the beneficial level. For example, in this embodiment, histamine can be administered whenever the subject""s histamine levels drop below 0.2 xcexcM. Alternatively, it will be appreciated that histamine can be administered at periodic intervals at dosages sufficient to establish and maintain beneficial levels.
Routes and carrier compositions for administering histamine have been disclosed in U.S. Pat, Nos. 5,348,739 and 5,728,378, which are incorporated herein by reference. Controlled release vehicles are also well-known to those of skill in the pharmaceutical sciences. The technology and products in this art are variably referred to as controlled release, sustained release, prolonged action, depro, repository, delayed action, retarded release and time release; the words xe2x80x9ccontrolled releasexe2x80x9d as used herein is intended to incorporate each of the foregoing technologies. U.S. patent application Ser. No. 08/767,338 also discloses numerous controlled release vehicles as well as infusion devices for use in the administration of histamine.
Preferably, the histamine is injected, infused or released into the patient at a rate of from about 0.5 to 0.2 mg per minute. A rate of about 0.1 mg per minute is preferred. The histamine is preferably administered over a period of time ranging from about 1, 3 or 5 minutes to about 30 minutes, with an upper limit of about 20 minutes being preferred, such that the total daily adult dose of histamine ranges from between about 0.1 to about 10.0 mg, with about 1.0 to about 5.0 mg being preferred. Histamine administered over longer periods of time (i.e., longer than about 30 minutes) has been found to result in a decrease or lack of efficacy, while rapid administration over less than 1 to 3 minutes can cause more pronounced and serious sides effects, which include anaphalaxis, heart failure, broncospasm, pronounced flushing, discomfort, increased heart rate and respiratory rate, hypertension, and severe headache.
Administration of each dose of histamine can occur from once a day to up to about four times a day, with twice a day being preferred. Administration can be subcutaneous, intravenous, intramuscular, intraoccular, oral, transmucosal, or transdermal, and can utilize direct hypodermic or other injection or infusion means, or can be mediated by a controlled release mechanism of the type disclosed above. Any controlled release vehicle or infusion device capable of administering a therapeutically effective amount of histamine over a period of time ranging from about 1 to about 30 minutes can be used.
In addition to histamine, histamine dihydrochloride, histamine phosphate, or other histamine salts, esters, congeners, prodrugs and histamine receptor agonists, the use of seratonin, 5HT agonists, and compounds which induce the release of histamine from the patient""s own tissues is also included within the scope of the present invention. Retinoic acid, other retinoids such as 9-cis-retinoic acid and all-trans-retinoic acid, IL-3 and ingestable allergens are compounds which are known to induce the release of endogenous histamine. These compounds can be administered to the patient by oral, intravenous, intramuscular, subcutaneous or other approved routes. However, the administration of the compound which induces the release of histamine from the patient""s own tissue should result in a release of endogenous histamine in the range of from about 0.1 to 10.0 mg/day , preferably around 0.5 to 8.0 mg/day and more preferably around 1.0 to 5.0 mg/day.
Administration of each dose of a compound which induces histamine release can occur from once per day to up to about 4 times per day, with twice per day being preferred. Administration can be subcutaneous, intravenous, intramuscular, intraoccular, oral, transmucosal, or transdermal, and can incorporate a controlled released mechanism of the type disclosed above. Any controlled release vehicle capable of administering a therapeutically effective amount of a compound which induces histamine release over a period of time ranging from about 1 to about 30 minutes can be used.
Malignancies against which the treatment may be directed include, but are not limited to, primary and metastic malignant solid tumor disease, and hematological malignancies such as acute and chronic myelogenous leukemia, acute and chronic lymphatic leukemia, multiple myeloma, Waldenstrom""s macroglobulinemia, hairy cell leukemia, myelodisplastic syndrome, polycytaemia vera, and essential thrombocytosis.